US9339026B2 - Pneumatically agitated and aerated single-use bioreactor - Google Patents

Pneumatically agitated and aerated single-use bioreactor Download PDF

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Publication number
US9339026B2
US9339026B2 US13/523,646 US201213523646A US9339026B2 US 9339026 B2 US9339026 B2 US 9339026B2 US 201213523646 A US201213523646 A US 201213523646A US 9339026 B2 US9339026 B2 US 9339026B2
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gas
fluid
pneumatic motor
bag
sparger
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US20120252108A1 (en
Inventor
Sarfaraz K. Niazi
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Adello Biologics LLC
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Therapeutic Proteins International LLC
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Priority to PCT/US2013/045627 priority patent/WO2013188649A1/en
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0236—Mechanical aspects
    • A01N1/0263—Non-refrigerated containers specially adapted for transporting or storing living parts whilst preserving, e.g. cool boxes, blood bags or "straws" for cryopreservation
    • B01F15/00175—
    • B01F15/0022—
    • B01F15/00525—
    • B01F15/0085—
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
    • B01F27/80—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis
    • B01F27/808—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis with stirrers driven from the bottom of the receptacle
    • B01F3/04262—
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/20—Measuring; Control or regulation
    • B01F35/21—Measuring
    • B01F35/211—Measuring of the operational parameters
    • B01F35/2115—Temperature
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/20—Measuring; Control or regulation
    • B01F35/21—Measuring
    • B01F35/2132—Concentration, pH, pOH, p(ION) or oxygen-demand
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/30—Driving arrangements; Transmissions; Couplings; Brakes
    • B01F35/32—Driving arrangements
    • B01F35/32005—Type of drive
    • B01F35/3203—Gas driven
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/50—Mixing receptacles
    • B01F35/513—Flexible receptacles, e.g. bags supported by rigid containers
    • B01F7/162—
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M23/00—Constructional details, e.g. recesses, hinges
    • C12M23/02—Form or structure of the vessel
    • C12M23/14—Bags
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M23/00—Constructional details, e.g. recesses, hinges
    • C12M23/28—Constructional details, e.g. recesses, hinges disposable or single use
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M27/00—Means for mixing, agitating or circulating fluids in the vessel
    • C12M27/02—Stirrer or mobile mixing elements
    • C12M27/04—Stirrer or mobile mixing elements with introduction of gas through the stirrer or mixing element
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/20—Mixing gases with liquids
    • B01F23/23—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids
    • B01F23/231—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids by bubbling
    • B01F23/23105—Arrangement or manipulation of the gas bubbling devices
    • B01F23/2312—Diffusers
    • B01F23/23123—Diffusers consisting of rigid porous or perforated material

Definitions

  • the present invention relates generally to vessels in which fluids are agitated and, more particularly, to a bioreactor.
  • one of the bioprocessing steps used in such manufacturing is growing cell culture(s) in the container, sometimes called a “bioreactor.”
  • a traditional bioreactor is a sterile vessel made out of stainless steel or glass with highly controlled environmental parameters including temperature, pH, oxygen concentration, carbon dioxide concentration, which are monitored by permanent sensors built into the rigid vessel.
  • the fluid in the bioreactor must also be agitated in order to maintain uniform distribution of temperature, gases and nutrients.
  • an impeller typically provides agitation with the blades housed on the shaft connected to an external motor and introduced inside the bioreactor through the dynamic seal in an effort to maintain sterility.
  • porous solid materials like titanium
  • metal sparging rings with small pre-drilled holes are permanently affixed in some rigid bioreactors. In both cases, the bioreactors are not readily disposable and thus must be cleaned and sterilized before reuse for bioprocessing.
  • a bioreactor plastic bag (which is basically thin film) has no shape or structural rigidity.
  • bioreactor components like impeller shafts, spargers, sensors are housed on the rigid walls of the vessel by means of threads, bolts or clamps.
  • this method of component attachment does not work for plastic bags.
  • many manufacturers offer such solutions as levitating mixing devices, rocking and shaking of bags or compressing the bag externally to produce a wave motion inside the bag. While all of these methods provide some solutions to the problem, many problems in the mixing and aeration remain.
  • a disposable bioprocessing apparatus intended for receiving a fluid in need of agitation and sparging using a gas.
  • the apparatus comprises a bag having an upper and a lower flexible wall forming an interior compartment capable of receiving and holding the fluid; a sparger positioned in the interior compartment for forming bubbles from the gas supplied to the fluid when present in the interior compartment; and a fluid-agitating element positioned at the inside bottom of the bag for agitating the fluid radially to assure optimal mixing and assisting in distributing the bubbles throughout the fluid when present in the interior compartment, wherein a rigid base connected to the bag for supporting the fluid-agitating is present.
  • the radial fluid-agitating element is driven by a disposable pneumatic vane motor to prevent any contact from any component from the outside of the bag, a critical step in preventing contamination of the components of the bag.
  • the bag is of round shape to prevent dead spots of mixing.
  • FIG. 1 is a side view of the bioreactor.
  • FIG. 2 is a detailed view of the top view of the bag.
  • FIG. 3 is a top view of the bioreactor.
  • FIG. 1 discloses one embodiment of the vessel of the present invention in the form of a bag 3 , which is flexible and of a round shape.
  • the bag 3 may be hermetically sealed and may have one or more openings or fittings 1 for introducing or recovering a fluid or exhausting a gas 2 or introducing gas (not shown here). Alternatively, the bag 3 may be unsealed or open-ended.
  • the particular geometry of the bag 3 employed is a round shape and is considered critical to the invention. Since the bag 3 is provided with an agitation system 8 that propels the liquid radially from the center to the periphery, having a round shape is required to eliminate any dead spots or unstirred pockets in the bag 3 .
  • FIG. 1 further shows the bag 3 containing a fluid 4 , a support system for the bag 3 and a heating or cooling element 6 and at least one sensor 7 to monitor the characteristics of the fluid 4 .
  • the flexible the bag 3 may be made from one or more sheets of thin (e.g., having a thickness of between 0.1 and 0.2 millimeters) polyethylene film secured together to define a compartment for receiving the fluid.
  • the film used is clear or translucent, although the use of opaque or colored films is also possible.
  • the fluid inside the bag 3 is agitated by a fluid-agitating element 8 , which is detailed in FIG. 2 .
  • the fluid-agitating element 8 comprises a radial impeller 10 affixed to a rotating surface 9 .
  • the fluid is discharged radially outward to the vessel wall.
  • radial flow impellers provide higher shear and turbulence levels. Radial flow draws the media from the top and bottom and can be used at high speed.
  • the most common impeller styles are the straight or vertical blade and crossed or curved (forward or backward) blade. Any of these types can be used, however, the curved blade provides the best mode of practice as it reduces the stress on the fluid.
  • the fluid-agitating element 8 is also depicted as including a plurality of blades to improve the degree of fluid agitation.
  • the particular number, type, and form of the vanes or blades are not considered important, as long as the desired degree of fluid agitation laterally towards the edges of the bag 3 is provided.
  • the size or the diameter of the fluid-agitating element is not important but conceivably it is of such size that the movement of liquid reaches to the edge of the bag using reasonable frequency of rotation that will not cause damage to the fluid content.
  • the diameter of the blade of fluid-agitating element 8 will be about 10-20% of the diameter of the bag 3 to obtain the maximum benefit of mixing.
  • the fluid-agitating element 8 is located in the center of the bag 3 and attached to the inside face of the lower layer of the bag 3 through a rigid plate 18 to keep the fluid-agitation element 8 from wobbling in the bag 3 .
  • the fluid-agitating element 8 is rotated using a pneumatically driven motor 15 as described in FIG. 2 .
  • pneumatic motors the pressure of compressed gas is converted to mechanical energy and comprises a working chamber and a set of vanes 12 .
  • the vanes are rotated resulting in the movement of the motor shaft 11 .
  • Vane air motor speed from 0 to 25,000 rev/min, working pressure of 0.4 ⁇ 0.8 MPa, and the power of 0.6 to 18 kW is readily achieved. Stepless speed changing the input flow can be realized.
  • a pneumatic motor can be used in the presence of fluid.
  • the pneumatic motor has a upper bearing 13 surrounding the shaft to allow swift movement at a high speed; these bearings can be traditional ball bearings or non-ball type bearings or sleeves of sufficient rigidity to withstand the repetitive motion of the shaft; at the bottom of the pneumatic motor, the shaft is connected to another lower bearing 13 to allow the shaft 11 to seat properly and allow swift movement.
  • the sparger 17 includes a porous surface attached to the exhaust 16 of the pneumatic motor having a porosity ranging from 1 micron to 100 microns. Additionally, porous surface can be provided before the entry point of gas in the pneumatic motor, where the sparging from one source of the sparger is not sufficient, a situation that is more likely to arise when fermenting bacteria.
  • the sparging surface can be made from stainless steel, perforated plastic, a membrane or aluminum oxide or any other hard or soft surface capable diffusing gas out as fine bubbles.
  • the source of energy utilized to turn the pneumatic motor is also utilized to provide aeration of the fluid, making the salient features of the instant invention most energy optimized.
  • the fluid-agitating element 8 is affixed to a hard surface 18 , which in turn is attached to the interior surface of the bottom sheet of the bag 3 . This allows the fluid-agitating element 8 to stay upright during operation.
  • bag 3 Once use of the bag 3 is complete, it may then simply be discarded along with the sparger 10 and fluid-agitation device 8 and the pneumatic motor 6 .
  • a sparger 17 and/or a pneumatic fluid-agitating element 8 it may also be desirable to provide disposable means in the bag 3 to facilitate sensing characteristics of the fluid, such as the pH, oxygen content, temperature, etc.
  • these sensors 7 FIG. 1
  • these sensors 7 are of disposable type and embedded in the bag 3 and remote receivers monitor the response to the sensors.
  • FIG. 3 shows a topical view of the bioreactor wherein the round shape of the bag 3 and the location of the fluid agitating element 8 is described.

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Abstract

A single-use round flexible mixing bag for use in bioprocessing in which a fluid is received and agitated using an internal fluid-agitating element comprising a radial flow impeller driven by an internal pneumatic vane motor is disclosed. The bag may include an integral sparger and sensor receiver. Related methods are also disclosed.

Description

TECHNICAL FIELD
The present invention relates generally to vessels in which fluids are agitated and, more particularly, to a bioreactor.
BACKGROUND OF THE INVENTION
Most pharmaceutical solutions and suspensions manufactured on an industrial scale require highly controlled, thorough mixing to achieve a satisfactory yield and ensure a uniform distribution of ingredients in the final product. Agitator tanks are frequently used to complete the mixing process, but a better degree of mixing is normally achieved by using a mechanical stirrer or impeller (e.g., a set of mixing blades attached to a metal rod). Typically, the mechanical stirrer or impeller is simply lowered into the fluid through an opening in the top of the vessel and rotated by an external motor to create the desired mixing action.
One significant limitation or shortcoming of such an arrangement is the danger of contamination or leakage during mixing. The rod carrying the mixing blades or impeller is typically introduced into the vessel through a dynamic seal or bearing. This opening provides an opportunity for bacteria or other contaminants to enter, which of course can lead to the degradation of the product. A corresponding danger of environmental contamination exists in applications involving hazardous or toxic fluids, or suspensions of pathogenic organisms, since dynamic seals or bearings are prone to leakage. Cleanup and sterilization are also made difficult by the dynamic bearings or seals, since these structures typically include folds and crevices that are difficult to reach. Since these problems are faced by all manufacturers of sterile solutions, pharmaceuticals, or the like, the U.S. Food and Drug Administration (FDA) has consequently promulgated strict processing requirements for such fluids, and especially those slated for intravenous use.
In an effort to overcome these problems, the recent trend in the biotechnology industry is to use disposable plastic bags for a number of bioprocessing steps. Pre-sterilized disposable plastic bags eliminate the need for cleaning, sterilization and validation of the containers after each bioprocessing batch. Their use thus results in substantial saving in the cost of manufacturing of biopharmaceuticals.
Typically, one of the bioprocessing steps used in such manufacturing is growing cell culture(s) in the container, sometimes called a “bioreactor.” A traditional bioreactor is a sterile vessel made out of stainless steel or glass with highly controlled environmental parameters including temperature, pH, oxygen concentration, carbon dioxide concentration, which are monitored by permanent sensors built into the rigid vessel. During the cell growth process, the fluid in the bioreactor must also be agitated in order to maintain uniform distribution of temperature, gases and nutrients. As noted above, an impeller typically provides agitation with the blades housed on the shaft connected to an external motor and introduced inside the bioreactor through the dynamic seal in an effort to maintain sterility.
For normal cell growth certain concentration of dissolved oxygen must be maintained. Also, controlled introduction of other gases like carbon dioxide and nitrogen are normally necessary during bioreactor runs. The most efficient way of introducing gases in to bioreactor fluid is sparging, which involves forming small bubbles in the fluid. Such bubbles have large surface to volume ratio and thus can be dissolved more quickly than large size bubbles and thus provide a large kLA value (transport across liquid air interface).
Traditionally, porous solid materials (like titanium) associated with the rigid bioreactor provide sparging. Alternatively, metal sparging rings with small pre-drilled holes are permanently affixed in some rigid bioreactors. In both cases, the bioreactors are not readily disposable and thus must be cleaned and sterilized before reuse for bioprocessing.
In traditional rigid vessel bioreactor, the impeller, sparger, gas, temperature and pH sensors are reusable components that must be cleaned and sterilized after each batch. In the case of disposable bag bioreactors, it is desirable that all the fluid touching components are only used once. This presents the challenging task of providing inexpensive fluid-touching components that can be discarded along with the bag after use.
Another challenge is positioning the components of the bioreactor on the flexible bag. Unlike a rigid vessel, a bioreactor plastic bag (which is basically thin film) has no shape or structural rigidity. Traditionally, bioreactor components like impeller shafts, spargers, sensors are housed on the rigid walls of the vessel by means of threads, bolts or clamps. Obviously, this method of component attachment does not work for plastic bags. To overcome this, many manufacturers offer such solutions as levitating mixing devices, rocking and shaking of bags or compressing the bag externally to produce a wave motion inside the bag. While all of these methods provide some solutions to the problem, many problems in the mixing and aeration remain.
Thus, a need is identified for an improved manner of providing a mixing bag or flexible vessel with an integrated sparger and sensor(s). The improvement provided by the invention would be easy to implement using existing manufacturing techniques and without significant additional expense. Overall, a substantial gain in efficiency and ease of use would be realized as a result of the improvement, and would greatly expand the potential applications for which advanced mixing systems may be used, including bioprocessing.
BRIEF SUMMARY OF THE INVENTION
A disposable bioprocessing apparatus intended for receiving a fluid in need of agitation and sparging using a gas is provided. The apparatus according to one aspect of the disclosure comprises a bag having an upper and a lower flexible wall forming an interior compartment capable of receiving and holding the fluid; a sparger positioned in the interior compartment for forming bubbles from the gas supplied to the fluid when present in the interior compartment; and a fluid-agitating element positioned at the inside bottom of the bag for agitating the fluid radially to assure optimal mixing and assisting in distributing the bubbles throughout the fluid when present in the interior compartment, wherein a rigid base connected to the bag for supporting the fluid-agitating is present. The radial fluid-agitating element is driven by a disposable pneumatic vane motor to prevent any contact from any component from the outside of the bag, a critical step in preventing contamination of the components of the bag. In one embodiment, the bag is of round shape to prevent dead spots of mixing.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a side view of the bioreactor.
FIG. 2 is a detailed view of the top view of the bag.
FIG. 3 is a top view of the bioreactor.
 DETAILED DESCRIPTION OF THE INVENTION
Reference is now made to FIG. 1, which discloses one embodiment of the vessel of the present invention in the form of a bag 3, which is flexible and of a round shape. The bag 3 may be hermetically sealed and may have one or more openings or fittings 1 for introducing or recovering a fluid or exhausting a gas 2 or introducing gas (not shown here). Alternatively, the bag 3 may be unsealed or open-ended. The particular geometry of the bag 3 employed is a round shape and is considered critical to the invention. Since the bag 3 is provided with an agitation system 8 that propels the liquid radially from the center to the periphery, having a round shape is required to eliminate any dead spots or unstirred pockets in the bag 3. For specific applications, in the case of a sterile fluid, a hermetically sealed, pre-sterilized bag with an aseptic fitting might be desirable; whereas, in the case where sterility is not important, an open-ended or unsealed bag might be suitable. The main important point is that the bag 3 is capable of receiving and at least temporarily holding a fluid (which is used herein to denote any substance capable of flowing, as may include liquids, liquid suspensions, gases, gaseous suspensions, or the like, without limitation). FIG. 1 further shows the bag 3 containing a fluid 4, a support system for the bag 3 and a heating or cooling element 6 and at least one sensor 7 to monitor the characteristics of the fluid 4.
The flexible the bag 3 may be made from one or more sheets of thin (e.g., having a thickness of between 0.1 and 0.2 millimeters) polyethylene film secured together to define a compartment for receiving the fluid. Preferably, the film used is clear or translucent, although the use of opaque or colored films is also possible.
The fluid inside the bag 3 is agitated by a fluid-agitating element 8, which is detailed in FIG. 2. In the embodiment of FIG. 2, the fluid-agitating element 8 comprises a radial impeller 10 affixed to a rotating surface 9. The fluid is discharged radially outward to the vessel wall. Compared to axial flow impellers, radial flow impellers provide higher shear and turbulence levels. Radial flow draws the media from the top and bottom and can be used at high speed. The most common impeller styles are the straight or vertical blade and crossed or curved (forward or backward) blade. Any of these types can be used, however, the curved blade provides the best mode of practice as it reduces the stress on the fluid. The fluid-agitating element 8 is also depicted as including a plurality of blades to improve the degree of fluid agitation. The particular number, type, and form of the vanes or blades are not considered important, as long as the desired degree of fluid agitation laterally towards the edges of the bag 3 is provided.
As explained above, it may be desirable to fix the general location or position of the fluid-agitating element 8 within the bag 3; the size or the diameter of the fluid-agitating element is not important but conceivably it is of such size that the movement of liquid reaches to the edge of the bag using reasonable frequency of rotation that will not cause damage to the fluid content. In most instances, the diameter of the blade of fluid-agitating element 8 will be about 10-20% of the diameter of the bag 3 to obtain the maximum benefit of mixing. In accordance with a second aspect of the invention, the fluid-agitating element 8 is located in the center of the bag 3 and attached to the inside face of the lower layer of the bag 3 through a rigid plate 18 to keep the fluid-agitation element 8 from wobbling in the bag 3.
The fluid-agitating element 8 is rotated using a pneumatically driven motor 15 as described in FIG. 2. In pneumatic motors, the pressure of compressed gas is converted to mechanical energy and comprises a working chamber and a set of vanes 12. When the compressed gas from the inlet 14 enters into the working chamber, the vanes are rotated resulting in the movement of the motor shaft 11. Vane air motor speed from 0 to 25,000 rev/min, working pressure of 0.4˜0.8 MPa, and the power of 0.6 to 18 kW is readily achieved. Stepless speed changing the input flow can be realized. A pneumatic motor can be used in the presence of fluid. It is noteworthy that the pneumatic motor has a upper bearing 13 surrounding the shaft to allow swift movement at a high speed; these bearings can be traditional ball bearings or non-ball type bearings or sleeves of sufficient rigidity to withstand the repetitive motion of the shaft; at the bottom of the pneumatic motor, the shaft is connected to another lower bearing 13 to allow the shaft 11 to seat properly and allow swift movement.
Turning now to FIG. 2, and as noted in the foregoing description, it may also be desirable to provide the bag 3 with an integral sparger 17 including means for forming bubbles in the fluid. In the illustrated embodiment, the sparger 17 includes a porous surface attached to the exhaust 16 of the pneumatic motor having a porosity ranging from 1 micron to 100 microns. Additionally, porous surface can be provided before the entry point of gas in the pneumatic motor, where the sparging from one source of the sparger is not sufficient, a situation that is more likely to arise when fermenting bacteria. The sparging surface can be made from stainless steel, perforated plastic, a membrane or aluminum oxide or any other hard or soft surface capable diffusing gas out as fine bubbles. In this capacity, the source of energy utilized to turn the pneumatic motor is also utilized to provide aeration of the fluid, making the salient features of the instant invention most energy optimized. The fluid-agitating element 8 is affixed to a hard surface 18, which in turn is attached to the interior surface of the bottom sheet of the bag 3. This allows the fluid-agitating element 8 to stay upright during operation.
Once use of the bag 3 is complete, it may then simply be discarded along with the sparger 10 and fluid-agitation device 8 and the pneumatic motor 6.
Besides a sparger 17 and/or a pneumatic fluid-agitating element 8, it may also be desirable to provide disposable means in the bag 3 to facilitate sensing characteristics of the fluid, such as the pH, oxygen content, temperature, etc. Preferably these sensors 7 (FIG. 1) are of disposable type and embedded in the bag 3 and remote receivers monitor the response to the sensors.
FIG. 3 shows a topical view of the bioreactor wherein the round shape of the bag 3 and the location of the fluid agitating element 8 is described.
The foregoing descriptions of various embodiments of the present inventions have been presented for purposes of illustration and description. These descriptions are not intended to be exhaustive or to limit the invention to the precise forms disclosed. The embodiments described provide the best illustration of the principles of the invention and its practical applications to thereby enable one of ordinary skill in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. All such modifications and variations are within the scope of the invention as determined by the appended claims when interpreted in accordance with the breadth to which they are fairly, legally and equitably entitled.

Claims (11)

The invention claimed is:
1. A disposable bioprocessing apparatus intended for receiving a fluid in need of agitation and sparging using a gas, comprising:
a round, flexible bag having a round upper sheet with an interior and an exterior surface and an edge and a round lower sheet with an interior and an exterior surface and an edge and wherein the edge of the upper sheet and the edge of the lower sheet are sealed together to form a cavity capable of receiving and holding the fluid;
a gas-driven fluid agitating element for agitating the fluid and assisting in distributing the bubbles comprising a pneumatic motor with a gas inlet and a gas outlet, a shaft and at least one rotating blade attached to the shaft, wherein said gas-driven fluid agitating element is located inside the flexible bag;
a hard support surface affixed at the center of the interior surface of the lower sheet of the bag and to which the gas-driven fluid agitating element is fixed;
a source of compressed gas fluidly connected to the gas inlet of the pneumatic motor, the source of compressed gas supplying compressed gas to the pneumatic motor to drive the at least one rotating blade to agitate the fluid;
a sparger fluidly connected to the gas outlet of the pneumatic motor for forming bubbles, the sparger receiving exhaust gas from the pneumatic motor and aerating the fluid in the bag with the exhaust gas;
a source of compressed gas to operate the pneumatic motor;
a support surface to hold the bag;
at least one liquid port; and
at least one gas port.
2. The apparatus according to claim 1, further including a sensor for sensing a condition of the fluid in the bag.
3. The apparatus according to claim 1, further including a means of heating or cooling the fluid in the bag.
4. The apparatus according to claim 1, wherein the rotating blade moves the fluid in a radial direction.
5. The apparatus according to claim 1, wherein the pneumatic motor contains vanes rotated by the flow of gas.
6. A disposable bioprocessing apparatus comprising:
(a) a round, flexible bag comprising a nutrient medium comprising a recombinant organism;
(b) a gas-driven fluid-agitating element for agitating fluid located inside the flexible bag and assisting in distributing bubbles comprising a pneumatic motor with a gas inlet and a gas outlet, a shaft and at least one rotating blade attached to the shaft;
(c) a hard support surface affixed at the center of the interior surface of the lower sheet of the bag and to which the gas-driven fluid agitating element is fixed;
(d) a source of compressed gas fluidly connected to the gas inlet of the pneumatic motor, the source of compressed gas supplying compressed gas to the pneumatic motor to drive the at least one rotating blade to agitate the fluid;
(e) a sparger fluidly connected to the gas outlet of the pneumatic motor for forming bubbles, the sparger receiving exhaust gas from the pneumatic motor and aerating the fluid in the bag with the exhaust gas;
(f) at least one liquid port; and
(g) at least one gas port.
7. The apparatus according to claim 6, wherein the recombinant organism is a bacterium, an animal cell, a plant cell, a virus, or a yeast cell.
8. The apparatus according to claim 6, wherein the recombinant organism is capable of expressing a recombinant protein or antibody.
9. A disposable bioprocessing apparatus comprising:
(a) a round, flexible bag containing a buffer;
(b) a gas-driven fluid-agitating element for agitating fluid located inside the flexible bag and assisting in distributing bubbles comprising a pneumatic motor with a gas inlet and a gas outlet, a shaft and at least one rotating blade attached to the shaft;
(c) a hard support surface affixed at the center of the interior surface of the lower sheet of the bag and to which the gas-driven fluid agitating element is fixed;
(d) a source of compressed gas fluidly connected to the gas inlet of the pneumatic motor, the source of compressed gas supplying compressed gas to the pneumatic motor to drive the at least one rotating blade to agitate the fluid;
(e) a sparger fluidly connected to the gas outlet of the pneumatic motor for forming bubbles, the sparger receiving exhaust gas from the pneumatic motor and aerating the fluid in the bag with the exhaust gas;
(f) at least one liquid port; and
(g) at least one gas port.
10. A disposable bioprocessing apparatus comprising:
(a) a round, flexible bag containing a dilute solution of proteins in need of refolding;
(b) a gas-driven fluid-agitating element for agitating fluid located inside the flexible bag and assisting in distributing bubbles comprising a pneumatic motor with a gas inlet and a gas outlet, a shaft and at least one rotating blade attached to the shaft;
(c) a hard support surface affixed at the center of the interior surface of the lower sheet of the bag and to which the gas-driven fluid agitating element is fixed;
(d) a source of compressed gas fluidly connected to the gas inlet of the pneumatic motor, the source of compressed gas supplying compressed gas to the pneumatic motor to drive the at least one rotating blade to agitate the fluid;
(e) a sparger fluidly connected to the gas outlet of the pneumatic motor for forming bubbles, the sparger receiving exhaust gas from the pneumatic motor and aerating the fluid in the bag with the exhaust gas;
(f) at least one liquid port; and
(g) at least one gas port.
11. A disposable bioprocessing apparatus comprising:
(a) a round, flexible bag containing a body tissue or organ in need of oxygenation;
(b) a gas-driven fluid-agitating element for agitating fluid located inside the flexible bag and assisting in distributing bubbles comprising a pneumatic motor with a gas inlet and a gas outlet, a shaft and at least one rotating blade attached to the shaft;
(c) a hard support surface affixed at the center of the interior surface of the lower sheet of the bag and to which the gas-driven fluid agitating element is fixed;
(d) a source of compressed gas fluidly connected to the gas inlet of the pneumatic motor, the source of compressed gas supplying compressed gas to the pneumatic motor to drive the at least one rotating blade to agitate the fluid;
(e) a sparger fluidly connected to the gas outlet of the pneumatic motor for forming bubbles, the sparger receiving exhaust gas from the pneumatic motor and aerating the fluid in the bag with the exhaust gas;
(f) at least one liquid port; and
(g) at least one gas port.
US13/523,646 2012-06-14 2012-06-14 Pneumatically agitated and aerated single-use bioreactor Expired - Fee Related US9339026B2 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10213398B2 (en) * 2014-03-27 2019-02-26 Roland W. Winterfield Methods for alleviating statin myopathy

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107107001B (en) * 2014-12-31 2020-11-03 通用电气医疗集团生物科学公司 Shaft mounted fluid transfer assembly for disposable bioreactor
US10265668B2 (en) * 2016-01-29 2019-04-23 Sartorius Stedim Biotech Gmbh Mixing methods
CN107857230B (en) * 2017-12-20 2024-02-09 常熟市百联自动机械有限公司 Stirring filling equipment
CN110652903A (en) * 2019-09-24 2020-01-07 广东东荣金属制品有限公司 Ultra-high-speed rotating multi-cutter-head gas-liquid cutting mixing oxygenator
US11535421B2 (en) * 2019-12-30 2022-12-27 Global Life Sciences Solutions Usa Llc System and method for packaging a bioprocessing bag and associated components, and packaging for a bioprocessing bag
CN113509876B (en) * 2021-04-30 2023-09-26 广东丽臣奥威实业有限公司 Static mixer for surfactant

Citations (108)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1119370A (en) 1913-11-07 1914-12-01 Henry B Queal Rotary drink-mixer.
US1269189A (en) 1917-05-31 1918-06-11 Halbert L Kadish Method of recovering fertilizing material from tannery waste liquids.
US1505204A (en) 1922-03-16 1924-08-19 Thomas J Kiernan Carbonator
US2793166A (en) 1952-10-18 1957-05-21 Bristol Lab Inc Stirring device for laboratory fermenters
US3002895A (en) 1957-02-11 1961-10-03 Freedman David Incubator-shaker apparatus
DE2017472A1 (en) 1970-04-11 1971-11-04 Roehm Gmbh Magnetic agitator for small vessels
US3647397A (en) 1969-11-19 1972-03-07 Charles M Coleman Reagent solution preparation
US3677528A (en) 1970-12-31 1972-07-18 Shell Oil Co Fluid diffusion apparatus
US3900186A (en) 1973-07-13 1975-08-19 Wheaton Industries Magnetic cell stirrer
US3962892A (en) 1973-05-29 1976-06-15 Garlinghouse Leslie H Machine for controlled conditioning of liquids and mixtures
US4162855A (en) 1974-11-18 1979-07-31 Spectroderm International, Inc. Magnetic stirrer apparatus
US4209259A (en) 1978-11-01 1980-06-24 Rains Robert L Magnetic mixer
US4356967A (en) 1980-09-15 1982-11-02 Lunaire Environmental, Inc. Laboratory incubator chamber system
GB2076677B (en) 1980-04-23 1984-01-04 Thomas Thomas Ronal Magnetic stirring elements
DE3246330A1 (en) 1982-12-15 1984-06-20 Haagen & Rinau, 2800 Bremen Device for mixing at least two substances
EP0033292B1 (en) 1980-01-25 1984-07-25 Dubernard Hospital S.A. Device for artificial feeding
US4498785A (en) 1982-06-09 1985-02-12 Techne Corporation Floating magnetic stirrer for culture medium
DE3407370A1 (en) 1984-02-29 1985-08-29 Kurt Leistner Apparatus for introducing solid, liquid or gaseous treatment agent/nutrient into water, waste water
JPS6167476U (en) 1984-10-08 1986-05-09
JPS61212275A (en) 1985-03-16 1986-09-20 Shibaura Eng Works Co Ltd Bioreactor furnished with actuator
US4668632A (en) 1985-02-06 1987-05-26 Vxr, Inc. Sparger and apparatus for and method of growing cells
US4711582A (en) 1986-11-07 1987-12-08 Kennedy Richard B Rotary mixing of two component resins in disposable plastic bag
GB2202549A (en) 1987-03-20 1988-09-28 Philip John Whitney Foldable fermenter
JPS63242297A (en) 1987-03-31 1988-10-07 ジューキ株式会社 Automatic sewing machine
US4783172A (en) 1985-10-03 1988-11-08 Garg Raj P Respirometer
US4808348A (en) 1987-05-14 1989-02-28 The Coca-Cola Company Microgravity carbonator
US4870018A (en) 1984-08-03 1989-09-26 Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) Process and apparatus for gassing liquids
EP0343885A1 (en) 1988-05-19 1989-11-29 P.B. Ind. Plant Biotech Industries Ltd. Air lift fermentor formed from flexible plastic sheets
DE3818776A1 (en) 1988-06-02 1989-12-07 Maerkl Herbert Process for the cultivation of cells in a fermenter, and fermenter intended for carrying out the process
EP0200792B1 (en) 1985-02-01 1990-05-09 Herbert Prof. Dr.-Ing. Märkl Foil fermenter
US4978616A (en) 1985-02-28 1990-12-18 Verax Corporation Fluidized cell cultivation process
US5008197A (en) 1983-11-10 1991-04-16 Ivar Wergeland Process and a device for improved oxygenation of biological cultures
US5061448A (en) 1988-04-29 1991-10-29 Barnstead Thermolyne Corporation Incubator
US5205783A (en) 1991-08-22 1993-04-27 Accu*Aire Systems, Inc. Air flow control equipment in chemical laboratory buildings
USRE34386E (en) 1986-07-18 1993-09-21 National Research Development Corporation Impeller
US5270207A (en) 1989-06-26 1993-12-14 Meiji Milk Products Company Limited Circulatory culture equipment
US5401212A (en) 1990-08-29 1995-03-28 Intelligent Enclosures Corporation Environmental control system
US5501971A (en) 1993-01-29 1996-03-26 New Brunswick Scientific Co., Inc. Method and apparatus for anchorage and suspension cell culture
CA2271583A1 (en) 1995-02-13 1996-08-14 Rodney S. Kenley Modular home dialysis system
EP0590473B1 (en) 1992-10-01 1996-12-11 Mavag Verfahrenstechnik Ag Impeller for stirring sterile liquids
DE19542227A1 (en) 1995-11-13 1997-05-15 Norman Kunz Packaging for materials sensitive to air contact
US5656491A (en) 1992-06-09 1997-08-12 Snamprogettibiotecnologie S.P.A. Mobile-module plant for the development and the production of biotechnological products on a pilot scale
DE29800818U1 (en) 1997-12-02 1998-03-12 Stelzer Rührtechnik GmbH, 34414 Warburg Magnetic stirrer
US5727878A (en) 1996-10-17 1998-03-17 Cdf Corporation Liner for a mixing container and an assembly and method for mixing fluid components
US5750440A (en) 1995-11-20 1998-05-12 Motorola, Inc. Apparatus and method for dynamically mixing slurry for chemical mechanical polishing
US5779359A (en) 1996-12-05 1998-07-14 General Signal Corporation Mixer having exposed clean-in-place bearing assemblies
WO1998033538A1 (en) 1997-02-04 1998-08-06 Novo Nordisk A/S A device for the administration of a liquid medicament suspension
US5803137A (en) 1995-07-24 1998-09-08 Beldex Corporation Liquid crystal delivering apparatus
JPH10314569A (en) 1997-05-16 1998-12-02 Hiroshi Miyauchi Agitating device
JPH10313718A (en) 1997-05-22 1998-12-02 Toshiba Eng & Constr Co Ltd Plant piece culturing device and method therefor
WO1998052629A3 (en) 1997-05-20 1999-02-25 Zymequest Inc Cell processing systems
US5939313A (en) 1997-09-12 1999-08-17 Praxair Technology, Inc. Stationary vortex system for direct injection of supplemental reactor oxygen
US5941635A (en) 1997-06-11 1999-08-24 Hyclone Labortories, Inc. Mixing block for resuspension system
US5988422A (en) 1998-07-16 1999-11-23 Stedim, Z.I. Des Paluds Sachets for bio-pharmaceutical fluid products
WO2000011953A1 (en) 1998-09-01 2000-03-09 Penn State Research Foundation Method and apparatus for aseptic growth or processing of biomass
US6036357A (en) * 1996-07-19 2000-03-14 Van Drie; Gerhardt Woodrow Submarine-type liquid mixer
DE19705118C2 (en) 1997-02-11 2000-03-30 Vorlop Klaus Dieter Agitator, radial seal-free, for unpressurized as well as for pressurized and temperature loaded containers
US6071005A (en) 1996-06-11 2000-06-06 Merck & Co., Inc. Disposable storage, transport and resuspension system
US6247840B1 (en) 1998-01-15 2001-06-19 Shaik A. Gaffar Dialysis container with sample saver
DE20114076U1 (en) 2001-08-29 2001-10-25 Hebold Gmbh & Co Kg App Und An Homogenizer, especially for the bottom of a mixing and stirring tank
US20010039369A1 (en) 1999-12-14 2001-11-08 Terentiev Alexandre N. Blood pump system
FR2799138B1 (en) 1999-10-05 2002-02-08 Opifex REACTOR FOR THE PRODUCTION OF CELL CULTURES OR MICROORGANISMS OR FOR THE SOLUTION OR SUSPENSION OF POWDER IN A LIQUID MEDIUM
US6357907B1 (en) 1999-06-15 2002-03-19 V & P Scientific, Inc. Magnetic levitation stirring devices and machines for mixing in vessels
US6379625B1 (en) 1999-12-23 2002-04-30 Peter Zuk, Jr. Apparatus comprising a disposable device and reusable instrument for synthesizing chemical compounds, and for testing chemical compounds for solubility
US6402367B1 (en) 2000-06-01 2002-06-11 Aemp Corporation Method and apparatus for magnetically stirring a thixotropic metal slurry
DE19917398C2 (en) 1999-04-16 2002-06-20 Accoris Gmbh Modular chemical microsystem
US20020082173A1 (en) 1999-01-04 2002-06-27 Terentiev Alexandre N. Pumping or mixing system using a levitating magnetic element
US20020091371A1 (en) 2001-01-08 2002-07-11 Ritter Franz Peter Salt container system for dialysis apparatus
US20020105856A1 (en) 2001-02-06 2002-08-08 Alexandre Terentiev Apparatus and method for mixing materials sealed in a container under sterile conditions
US6439756B1 (en) 1999-05-27 2002-08-27 EKATO Rühr- und Mischtechnik GmbH Agitator
US20020145940A1 (en) 2001-04-10 2002-10-10 Terentiev Alexandre N. Sterile fluid pumping or mixing system and related method
US6467946B1 (en) 2001-04-24 2002-10-22 Dade Microscan Inc. Method and apparatus for mixing liquid samples in a container using rotating magnetic fields
US6500343B2 (en) 1995-02-21 2002-12-31 Iqbal W. Siddiqi Method for mixing and separation employing magnetic particles
US20030008389A1 (en) 2001-07-09 2003-01-09 Carll Kenneth B. Disposable cell culture vessel
US6514137B1 (en) 1999-03-10 2003-02-04 Paul Giulo Panelli Modular clean room plenum
US6555011B1 (en) 1999-04-23 2003-04-29 Atlantium Ltd. Method for disinfecting and purifying liquids and gasses
US20030170810A1 (en) 2001-09-18 2003-09-11 Masoud Vedadi Methods and apparatuses for purification
US20030226857A1 (en) 2002-04-12 2003-12-11 Hyclone Laboratories, Inc. Systems for forming sterile fluid connections and methods of use
US20040027912A1 (en) * 2002-04-12 2004-02-12 Hynetics Llc Mixing tank assembly
US20040047232A1 (en) 2000-10-09 2004-03-11 Terentiev Alexandre N. System using a levitating, rotating pumping or mixing element and related methods
US20040062140A1 (en) 2002-09-27 2004-04-01 Cadogan David Phillip Bioprocess container, bioprocess container mixing device and method of use thereof
US6736906B2 (en) 2002-04-10 2004-05-18 International Business Machines Corporation Turbine part mount for supercritical fluid processor
US6764859B1 (en) 1999-07-19 2004-07-20 Biomerieux, B.V. Device and method for mixing magnetic particles with a fluid
US20040218468A1 (en) 2000-10-09 2004-11-04 Terentiev Alexandre N. Set-up kit for a pumping or mixing system using a levitating magnetic element
US20040221897A1 (en) 2003-05-09 2004-11-11 Stedim Disposable container for use in fluid processing
US20040229335A1 (en) 2003-05-15 2004-11-18 Introgen Therapeutics, Inc. Methods and compositions for the production of adenoviral vectors
US20040252582A1 (en) 2001-02-22 2004-12-16 Bucher Franz G Device for mixing and homogenizing materials in laboratory test container with a stirring element
US20050002274A1 (en) 2001-10-03 2005-01-06 Terentiev Alexandre N. Mixing bag or vessel having a receiver for a fluid-agitating element
US20050127215A1 (en) 2003-11-24 2005-06-16 Roche Diagnostics Operations, Inc. Device for comminuting agglomerates, in particular by breaking up microparticles by piston movement in a container
US20050163667A1 (en) 2004-01-26 2005-07-28 Krause Richard J. Single-use biobags with sendors: DO, pH, CO2 and temperature
WO2005068059A1 (en) 2004-01-07 2005-07-28 Levtech, Inc. Mixing bag with integral sparger and sensor receiver
WO2005037658A3 (en) 2003-10-14 2005-09-15 Advanced Tech Materials A flexible mixing bag for mixing solids, liquids and gases
US20050239199A1 (en) 2004-04-27 2005-10-27 Baxter International Inc. Stirred-tank reactor system
US20050272146A1 (en) 2004-06-04 2005-12-08 Geoffrey Hodge Disposable bioreactor systems and methods
WO2006002091A3 (en) 2004-06-23 2006-04-13 Levtech Inc Mixing vessel alignment systems, devices, and related methods
US20060092761A1 (en) 2000-10-09 2006-05-04 Terentiev Alexandre N Mixing vessel with a fluid-agitating element supported by a roller bearing
US20060270036A1 (en) 2005-04-22 2006-11-30 Hyclone Laboratories, Inc. Gas spargers and related container systems
WO2006063087B1 (en) 2004-12-09 2006-12-14 Levtech Inc Mixing vessel with a fluid-agitating element supported by a roller bearing
US7153021B2 (en) 2003-03-28 2006-12-26 Hyclone Laboratories, Inc. Container systems for mixing fluids with a magnetic stir bar
US20070036027A1 (en) * 2005-07-29 2007-02-15 Meier Hans P Magnetic agitator
WO2007039600A1 (en) 2005-10-04 2007-04-12 Artelis Method of cell cultures and device for implementing it
US20070201993A1 (en) 2006-02-28 2007-08-30 Terentiev Alexandre N Disposable pumping apparatus based on flexible vessels in pressurized containers
US20070220956A1 (en) 2006-03-22 2007-09-27 Terentiev Alexandre N Apparatus and methods for leak detection in bioprocessing bags
US20070263484A1 (en) 2000-10-09 2007-11-15 Terentiev Alexandre N Mixing bag or vessel with a fluid-agitating element
WO2008040568A1 (en) 2006-10-03 2008-04-10 Artelis Mixing system including a flexible bag, specific flexible bag and locating system for the mixing system
WO2008040567A1 (en) 2006-10-03 2008-04-10 Artelis Flexible mixing bag, mixing device and mixing system
US20090242173A1 (en) 2008-03-25 2009-10-01 Peter Mitchell Temperature control system
US20110013474A1 (en) 2008-03-19 2011-01-20 Sartorius Stedim Biotech Gmbh Disposable mixing vessel

Patent Citations (131)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1119370A (en) 1913-11-07 1914-12-01 Henry B Queal Rotary drink-mixer.
US1269189A (en) 1917-05-31 1918-06-11 Halbert L Kadish Method of recovering fertilizing material from tannery waste liquids.
US1505204A (en) 1922-03-16 1924-08-19 Thomas J Kiernan Carbonator
US2793166A (en) 1952-10-18 1957-05-21 Bristol Lab Inc Stirring device for laboratory fermenters
US3002895A (en) 1957-02-11 1961-10-03 Freedman David Incubator-shaker apparatus
US3647397A (en) 1969-11-19 1972-03-07 Charles M Coleman Reagent solution preparation
DE2017472A1 (en) 1970-04-11 1971-11-04 Roehm Gmbh Magnetic agitator for small vessels
US3677528A (en) 1970-12-31 1972-07-18 Shell Oil Co Fluid diffusion apparatus
US3962892A (en) 1973-05-29 1976-06-15 Garlinghouse Leslie H Machine for controlled conditioning of liquids and mixtures
US3900186A (en) 1973-07-13 1975-08-19 Wheaton Industries Magnetic cell stirrer
US4162855A (en) 1974-11-18 1979-07-31 Spectroderm International, Inc. Magnetic stirrer apparatus
US4209259A (en) 1978-11-01 1980-06-24 Rains Robert L Magnetic mixer
EP0033292B1 (en) 1980-01-25 1984-07-25 Dubernard Hospital S.A. Device for artificial feeding
GB2076677B (en) 1980-04-23 1984-01-04 Thomas Thomas Ronal Magnetic stirring elements
US4356967A (en) 1980-09-15 1982-11-02 Lunaire Environmental, Inc. Laboratory incubator chamber system
US4498785A (en) 1982-06-09 1985-02-12 Techne Corporation Floating magnetic stirrer for culture medium
DE3246330A1 (en) 1982-12-15 1984-06-20 Haagen & Rinau, 2800 Bremen Device for mixing at least two substances
US5008197A (en) 1983-11-10 1991-04-16 Ivar Wergeland Process and a device for improved oxygenation of biological cultures
DE3407370A1 (en) 1984-02-29 1985-08-29 Kurt Leistner Apparatus for introducing solid, liquid or gaseous treatment agent/nutrient into water, waste water
US4870018A (en) 1984-08-03 1989-09-26 Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) Process and apparatus for gassing liquids
JPS6167476U (en) 1984-10-08 1986-05-09
EP0200792B1 (en) 1985-02-01 1990-05-09 Herbert Prof. Dr.-Ing. Märkl Foil fermenter
US4668632A (en) 1985-02-06 1987-05-26 Vxr, Inc. Sparger and apparatus for and method of growing cells
US4978616A (en) 1985-02-28 1990-12-18 Verax Corporation Fluidized cell cultivation process
JPS61212275A (en) 1985-03-16 1986-09-20 Shibaura Eng Works Co Ltd Bioreactor furnished with actuator
US4783172A (en) 1985-10-03 1988-11-08 Garg Raj P Respirometer
USRE34386E (en) 1986-07-18 1993-09-21 National Research Development Corporation Impeller
US4711582A (en) 1986-11-07 1987-12-08 Kennedy Richard B Rotary mixing of two component resins in disposable plastic bag
GB2202549A (en) 1987-03-20 1988-09-28 Philip John Whitney Foldable fermenter
JPS63242297A (en) 1987-03-31 1988-10-07 ジューキ株式会社 Automatic sewing machine
US4808348A (en) 1987-05-14 1989-02-28 The Coca-Cola Company Microgravity carbonator
US5061448A (en) 1988-04-29 1991-10-29 Barnstead Thermolyne Corporation Incubator
EP0343885A1 (en) 1988-05-19 1989-11-29 P.B. Ind. Plant Biotech Industries Ltd. Air lift fermentor formed from flexible plastic sheets
DE3818776A1 (en) 1988-06-02 1989-12-07 Maerkl Herbert Process for the cultivation of cells in a fermenter, and fermenter intended for carrying out the process
US5270207A (en) 1989-06-26 1993-12-14 Meiji Milk Products Company Limited Circulatory culture equipment
EP0433463B1 (en) 1989-06-26 1995-12-27 Meiji Milk Products Company Limited Rotary culture device
US5401212A (en) 1990-08-29 1995-03-28 Intelligent Enclosures Corporation Environmental control system
US5205783A (en) 1991-08-22 1993-04-27 Accu*Aire Systems, Inc. Air flow control equipment in chemical laboratory buildings
US5656491A (en) 1992-06-09 1997-08-12 Snamprogettibiotecnologie S.P.A. Mobile-module plant for the development and the production of biotechnological products on a pilot scale
EP0590473B1 (en) 1992-10-01 1996-12-11 Mavag Verfahrenstechnik Ag Impeller for stirring sterile liquids
US5501971A (en) 1993-01-29 1996-03-26 New Brunswick Scientific Co., Inc. Method and apparatus for anchorage and suspension cell culture
CA2271583A1 (en) 1995-02-13 1996-08-14 Rodney S. Kenley Modular home dialysis system
US5591344A (en) 1995-02-13 1997-01-07 Aksys, Ltd. Hot water disinfection of dialysis machines, including the extracorporeal circuit thereof
US6500343B2 (en) 1995-02-21 2002-12-31 Iqbal W. Siddiqi Method for mixing and separation employing magnetic particles
US5803137A (en) 1995-07-24 1998-09-08 Beldex Corporation Liquid crystal delivering apparatus
DE19542227A1 (en) 1995-11-13 1997-05-15 Norman Kunz Packaging for materials sensitive to air contact
US5750440A (en) 1995-11-20 1998-05-12 Motorola, Inc. Apparatus and method for dynamically mixing slurry for chemical mechanical polishing
US6071005A (en) 1996-06-11 2000-06-06 Merck & Co., Inc. Disposable storage, transport and resuspension system
US6036357A (en) * 1996-07-19 2000-03-14 Van Drie; Gerhardt Woodrow Submarine-type liquid mixer
US5727878A (en) 1996-10-17 1998-03-17 Cdf Corporation Liner for a mixing container and an assembly and method for mixing fluid components
US5779359A (en) 1996-12-05 1998-07-14 General Signal Corporation Mixer having exposed clean-in-place bearing assemblies
WO1998033538A1 (en) 1997-02-04 1998-08-06 Novo Nordisk A/S A device for the administration of a liquid medicament suspension
DE19705118C2 (en) 1997-02-11 2000-03-30 Vorlop Klaus Dieter Agitator, radial seal-free, for unpressurized as well as for pressurized and temperature loaded containers
JPH10314569A (en) 1997-05-16 1998-12-02 Hiroshi Miyauchi Agitating device
WO1998052629A3 (en) 1997-05-20 1999-02-25 Zymequest Inc Cell processing systems
JPH10313718A (en) 1997-05-22 1998-12-02 Toshiba Eng & Constr Co Ltd Plant piece culturing device and method therefor
US5941635A (en) 1997-06-11 1999-08-24 Hyclone Labortories, Inc. Mixing block for resuspension system
US5939313A (en) 1997-09-12 1999-08-17 Praxair Technology, Inc. Stationary vortex system for direct injection of supplemental reactor oxygen
DE29800818U1 (en) 1997-12-02 1998-03-12 Stelzer Rührtechnik GmbH, 34414 Warburg Magnetic stirrer
US6247840B1 (en) 1998-01-15 2001-06-19 Shaik A. Gaffar Dialysis container with sample saver
US5988422A (en) 1998-07-16 1999-11-23 Stedim, Z.I. Des Paluds Sachets for bio-pharmaceutical fluid products
WO2000011953A1 (en) 1998-09-01 2000-03-09 Penn State Research Foundation Method and apparatus for aseptic growth or processing of biomass
US6245555B1 (en) 1998-09-01 2001-06-12 The Penn State Research Foundation Method and apparatus for aseptic growth or processing of biomass
US20020082173A1 (en) 1999-01-04 2002-06-27 Terentiev Alexandre N. Pumping or mixing system using a levitating magnetic element
US6514137B1 (en) 1999-03-10 2003-02-04 Paul Giulo Panelli Modular clean room plenum
DE19917398C2 (en) 1999-04-16 2002-06-20 Accoris Gmbh Modular chemical microsystem
US6555011B1 (en) 1999-04-23 2003-04-29 Atlantium Ltd. Method for disinfecting and purifying liquids and gasses
US6439756B1 (en) 1999-05-27 2002-08-27 EKATO Rühr- und Mischtechnik GmbH Agitator
US6357907B1 (en) 1999-06-15 2002-03-19 V & P Scientific, Inc. Magnetic levitation stirring devices and machines for mixing in vessels
US6764859B1 (en) 1999-07-19 2004-07-20 Biomerieux, B.V. Device and method for mixing magnetic particles with a fluid
FR2799138B1 (en) 1999-10-05 2002-02-08 Opifex REACTOR FOR THE PRODUCTION OF CELL CULTURES OR MICROORGANISMS OR FOR THE SOLUTION OR SUSPENSION OF POWDER IN A LIQUID MEDIUM
US20010039369A1 (en) 1999-12-14 2001-11-08 Terentiev Alexandre N. Blood pump system
US6379625B1 (en) 1999-12-23 2002-04-30 Peter Zuk, Jr. Apparatus comprising a disposable device and reusable instrument for synthesizing chemical compounds, and for testing chemical compounds for solubility
US6402367B1 (en) 2000-06-01 2002-06-11 Aemp Corporation Method and apparatus for magnetically stirring a thixotropic metal slurry
US6637927B2 (en) 2000-06-01 2003-10-28 Innovative Products Group, Llc Method and apparatus for magnetically stirring a thixotropic metal slurry
US20070263484A1 (en) 2000-10-09 2007-11-15 Terentiev Alexandre N Mixing bag or vessel with a fluid-agitating element
US20050201201A1 (en) 2000-10-09 2005-09-15 Terentiev Alexandre N. Magnetic coupler for holding a magnetic pumping or mixing element in a vessel
US7762716B2 (en) 2000-10-09 2010-07-27 Levtech, Inc. Mixing vessel with a fluid-agitating element supported by a roller bearing
US20040218468A1 (en) 2000-10-09 2004-11-04 Terentiev Alexandre N. Set-up kit for a pumping or mixing system using a levitating magnetic element
US20060092761A1 (en) 2000-10-09 2006-05-04 Terentiev Alexandre N Mixing vessel with a fluid-agitating element supported by a roller bearing
US20040047232A1 (en) 2000-10-09 2004-03-11 Terentiev Alexandre N. System using a levitating, rotating pumping or mixing element and related methods
US20070030759A1 (en) 2000-10-09 2007-02-08 Terentiev Alexandre N Systems using a levitating, rotating pumping or mixing element and related methods
US20020091371A1 (en) 2001-01-08 2002-07-11 Ritter Franz Peter Salt container system for dialysis apparatus
US20020105856A1 (en) 2001-02-06 2002-08-08 Alexandre Terentiev Apparatus and method for mixing materials sealed in a container under sterile conditions
US20040252582A1 (en) 2001-02-22 2004-12-16 Bucher Franz G Device for mixing and homogenizing materials in laboratory test container with a stirring element
US20020145940A1 (en) 2001-04-10 2002-10-10 Terentiev Alexandre N. Sterile fluid pumping or mixing system and related method
US20050117449A1 (en) 2001-04-10 2005-06-02 Terentiev Alexandre N. Sterile fluid pumping or mixing system and related method
US6467946B1 (en) 2001-04-24 2002-10-22 Dade Microscan Inc. Method and apparatus for mixing liquid samples in a container using rotating magnetic fields
US6670171B2 (en) 2001-07-09 2003-12-30 Wheaton Usa, Inc. Disposable vessel
US20030008389A1 (en) 2001-07-09 2003-01-09 Carll Kenneth B. Disposable cell culture vessel
DE20114076U1 (en) 2001-08-29 2001-10-25 Hebold Gmbh & Co Kg App Und An Homogenizer, especially for the bottom of a mixing and stirring tank
US20030170810A1 (en) 2001-09-18 2003-09-11 Masoud Vedadi Methods and apparatuses for purification
WO2003028869A3 (en) 2001-10-03 2005-04-07 Levtech Inc Mixing bag or vessel having a receiver for a fluid-agitating element
US20050002274A1 (en) 2001-10-03 2005-01-06 Terentiev Alexandre N. Mixing bag or vessel having a receiver for a fluid-agitating element
US6736906B2 (en) 2002-04-10 2004-05-18 International Business Machines Corporation Turbine part mount for supercritical fluid processor
US20040027912A1 (en) * 2002-04-12 2004-02-12 Hynetics Llc Mixing tank assembly
US6923567B2 (en) 2002-04-12 2005-08-02 Hynetics Llc Mixing tank assembly
US20030226857A1 (en) 2002-04-12 2003-12-11 Hyclone Laboratories, Inc. Systems for forming sterile fluid connections and methods of use
US20040062140A1 (en) 2002-09-27 2004-04-01 Cadogan David Phillip Bioprocess container, bioprocess container mixing device and method of use thereof
US7278780B2 (en) 2003-03-28 2007-10-09 Hyclone Laboratories, Inc. Container systems for mixing fluids with a magnetic stir bar
EP1462155B1 (en) 2003-03-28 2007-05-09 Hyclone Laboratories, Inc. Container systems for mixing fluids with a magnetic stir bar
US7153021B2 (en) 2003-03-28 2006-12-26 Hyclone Laboratories, Inc. Container systems for mixing fluids with a magnetic stir bar
US20040221897A1 (en) 2003-05-09 2004-11-11 Stedim Disposable container for use in fluid processing
US20040229335A1 (en) 2003-05-15 2004-11-18 Introgen Therapeutics, Inc. Methods and compositions for the production of adenoviral vectors
WO2005037658A3 (en) 2003-10-14 2005-09-15 Advanced Tech Materials A flexible mixing bag for mixing solids, liquids and gases
US20050127215A1 (en) 2003-11-24 2005-06-16 Roche Diagnostics Operations, Inc. Device for comminuting agglomerates, in particular by breaking up microparticles by piston movement in a container
US20070252290A1 (en) 2004-01-07 2007-11-01 Terentiev Alexandre N Mixing bag with integral sparger and sensor receiver
US7384027B2 (en) 2004-01-07 2008-06-10 Levtech, Inc. Mixing bag with integral sparger and sensor receiver
US8123199B2 (en) 2004-01-07 2012-02-28 Atmi Packaging, Inc. Bioreactor
US20060131765A1 (en) 2004-01-07 2006-06-22 Terentiev Alexandre N Mixing bag with integral sparger and sensor receiver
US7992846B2 (en) 2004-01-07 2011-08-09 Atmi Packaging, Inc. Mixing bag with integral sparger and sensor receiver
US7469884B2 (en) 2004-01-07 2008-12-30 Levtech, Inc. Mixing bag with integral sparger and sensor receiver
WO2005068059A1 (en) 2004-01-07 2005-07-28 Levtech, Inc. Mixing bag with integral sparger and sensor receiver
US20050163667A1 (en) 2004-01-26 2005-07-28 Krause Richard J. Single-use biobags with sendors: DO, pH, CO2 and temperature
US7384783B2 (en) 2004-04-27 2008-06-10 Baxter International Inc. Stirred-tank reactor system
US20050239199A1 (en) 2004-04-27 2005-10-27 Baxter International Inc. Stirred-tank reactor system
US7629167B2 (en) 2004-06-04 2009-12-08 Xcellerex, Inc. Disposable bioreactor systems and methods
WO2005118771A3 (en) 2004-06-04 2006-02-02 Xcellerex Inc Disposable bioreactor systems and methods
US20050272146A1 (en) 2004-06-04 2005-12-08 Geoffrey Hodge Disposable bioreactor systems and methods
US20080008028A1 (en) 2004-06-23 2008-01-10 Levtech, Inc. Mixing vessel alignment systems, devices, and related methods
WO2006002091A3 (en) 2004-06-23 2006-04-13 Levtech Inc Mixing vessel alignment systems, devices, and related methods
WO2006063087B1 (en) 2004-12-09 2006-12-14 Levtech Inc Mixing vessel with a fluid-agitating element supported by a roller bearing
US20060270036A1 (en) 2005-04-22 2006-11-30 Hyclone Laboratories, Inc. Gas spargers and related container systems
US20070036027A1 (en) * 2005-07-29 2007-02-15 Meier Hans P Magnetic agitator
WO2007039600A1 (en) 2005-10-04 2007-04-12 Artelis Method of cell cultures and device for implementing it
US20070201993A1 (en) 2006-02-28 2007-08-30 Terentiev Alexandre N Disposable pumping apparatus based on flexible vessels in pressurized containers
US20070220956A1 (en) 2006-03-22 2007-09-27 Terentiev Alexandre N Apparatus and methods for leak detection in bioprocessing bags
WO2008040568A1 (en) 2006-10-03 2008-04-10 Artelis Mixing system including a flexible bag, specific flexible bag and locating system for the mixing system
WO2008040567A1 (en) 2006-10-03 2008-04-10 Artelis Flexible mixing bag, mixing device and mixing system
US20110013474A1 (en) 2008-03-19 2011-01-20 Sartorius Stedim Biotech Gmbh Disposable mixing vessel
US20090242173A1 (en) 2008-03-25 2009-10-01 Peter Mitchell Temperature control system

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
International Search Report and Written Opinion for PCT/US2012/045627 dated Nov. 22, 2013.
U.S. Appl. No. 60/535,031, filed Jan. 9, 2004, Terentiev.
U.S. Appl. No. 60/599,960, filed Aug. 9, 2004, Terentiev.

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10213398B2 (en) * 2014-03-27 2019-02-26 Roland W. Winterfield Methods for alleviating statin myopathy
US11147781B2 (en) 2014-03-27 2021-10-19 Roland W. Winterfield Methods for alleviating statin myopathy

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